We studied the referral pattern and diagnostic delay in a cohort of IPF patients and found that it was mainly attributable to patients, general practitioners and community hospitals. Previous inhalation therapy use was a major risk factor for a delayed diagnosis. Male sex was associated with a prolonged patient delay and older age was associated with a prolonged healthcare delay. Patients were often misdiagnosed and treated before a final diagnosis of IPF was made.
We present for the first time a detailed description of IPF patients’ path towards the IPF diagnosis and the different components of the diagnostic delay in incident patients and thus with limited recall bias. We highlight the three main sources of delay: patients themselves, general practitioners and community hospitals (most commonly departments of respiratory medicine). Future efforts to reduce the diagnostic delay should be directed at these three sources which could be achieved by further increasing awareness of IPF among patients, general practitioners and hospital physicians (both pulmonologists and other specialists). However, while the delay at ILD centres often was shorter, it still contributed to the total delay in many patients and the median time from the diagnostic HRCT until the final diagnosis was still 0.3 years. Therefore, there is a potential for interventions to shorten the delay at all steps towards the IPF diagnosis, which should be further explored. A delay, however, is not always the result of a mistake or missed diagnosis. It is possible that some patients were delayed because they did not fulfil diagnostic criteria for IPF during the early stages of their disease, which is a recognized limitation of the 2011 ATS/ERS/JRS/ALAT guidelines [16].
We expected a shortened diagnostic delay due to an increased awareness of IPF during recent years which unfortunately could not be confirmed. The availability of pharmacological treatments during the past few years resulted in an increase in the number of patients referred to ILD centres, but this increase has so far failed to impact the diagnostic delay in IPF [7]. We found a median total diagnostic delay of 2.1 years, which is similar to previous reports of IPF patients and general ILD populations, despite new treatment options, new diagnostic guidelines and increased awareness of IPF [4,5,6,7,8, 17,18,19,20].
In addition to the median length of the diagnostic delay of 2.1 years, we found a high spread of the specific and total delays with 25% of patients having a delay of more than 5 years. This finding contributes to the evolving understanding that some patients with IPF can have a slowly progressive phenotype [1]. However, some patients reported very long delays of up to 20 years, which are unlikely to be due to symptoms caused by IPF. Rather, the patient-reported symptoms could be caused by an alternative disease, such as cardiovascular disease or COPD, which are common comorbidities in patients with IPF [21]. In addition, recall bias can affect the patients’ ability to remember important information about the onset of their symptoms. However, the specific healthcare delays are defined by objective data from electronic records and support the hypothesis of a phenotype with slowly progressive IPF. The possible identification of interstitial lung abnormalities on lung CT many years prior to the development of clinical interstitial lung disease further contributes to this observation [22,23,24].
A first step to reduce the diagnostic delay is to identify risk factors for a delay and recognize target groups for interventions. We are unaware of previous studies providing estimates of risk factors for a delayed diagnosis of IPF. Interestingly, the risk factors for patient delay differ from those for healthcare delay. The previous use of inhalation therapy and male sex were risk factors for a prolonged patient delay. The increased delay in previous inhalation therapy users could be attributable to treatment attempts with inhalation therapy for unexplained respiratory symptoms in the primary care sector, which has been suggested previously [12, 18]. Airway obstruction was not a risk factor for a diagnostic delay, which indicates frequent futile treatment attempts with inhalation therapy in patients without obstructive lung disease. However, it is possible that an obstructive lung disease was masked by a concomitant reduction in FVC in some patients. While treatment attempts with inhalation therapy can be warranted in patients with unexplained respiratory symptoms, these patients should be closely monitored and referred for further workup when symptoms do not improve. In addition, a correctly performed and interpreted spirometry could help to quickly rule out airway obstruction as a cause of breathlessness in these patients. Improved diagnostic tools, including screening or effective diagnostic biomarkers, would make the diagnosis more accessible, also for non-ILD specialists, and are desperately needed.
Patients with a prolonged delay had relatively preserved DLCO at the time of diagnosis, suggesting that patients with more severe IPF were quickly diagnosed. On the other hand, patients with a prolonged delay reported a high symptom burden as indicated by a higher SGRQ total score. This apparent discrepancy could be explained by the complexity of quality of life data, which can be impacted by many factors, including a prolonged diagnostic delay but also by comorbidities, misdiagnosis, treatment and multiple healthcare contacts. Besides, the SGRQ total score has limitations in quantifying disease severity in IPF patients [25].
Patients reported frequent misdiagnosis prior to their final IPF diagnosis, which is in line with the presented risk factors for a diagnostic delay, and with previous patient surveys [12, 17, 20]. The frequent treatment with inhalation therapy for obstructive lung disease, despite the lack of airway obstruction, confirms this problem. In addition, the previous treatments were often given for long periods (median duration of treatment was 7.0 months) and included potentially harmful treatments such as prednisolone and other immunosuppressive drugs, which are often prescribed for other fibrotic lung disease such as chronic hypersensitivity pneumonitis, a common differential diagnosis to IPF. The frequent occurrences of pneumonia in the two years prior to the IPF diagnosis could either be due to an increased risk of infection in patients or misinterpretation of crackles on auscultation. Screening for finger clubbing and velcro crackles on auscultation, particularly if they do not resolve after treatment of suspected pneumonia, should prompt further diagnostic evaluation [26]. A treatment attempt for any suspected disease prolongs the diagnostic delay, and most importantly delays the initiation of effective antifibrotic treatment. Early referral of patients with an uncertain diagnosis to a centre with expertise in ILD is essential and could contribute to shortening the diagnostic delay.
Based on data from one participating centre, we could estimate an annual incidence of 2.9 IPF patients per 100,000 inhabitants per year. However, it might be suspected that some older and frail patients, or patients with severe comorbidities, were not referred for a diagnostic workup at an ILD centre. Our calculated incidence is in the lower end of the range of other estimates (0.6–17.4 cases of IPF per 100,000 inhabitants per year) which suggests a continuing underdiagnosis of IPF [27]. Previous reports have often been performed retrospectively or are based on registries and insurance claims (which can overestimate incidence due to miscoding) and many estimates predate the current diagnostic guidelines [27,28,29]. In contrast to several previous studies, all patients included in our cohort had a confident IPF diagnosis confirmed at a specialised ILD centre. A Danish study estimated the IPF incidence in 2003–2009 to be 1.3 patients per 100,000 inhabitants per year [7]. Thus, despite the apparent underdiagnosis, we can confirm a general increase in the incidence of IPF diagnosis in a comparable setting.
Our study has several strengths but also some limitations. A major strength is the prospective inclusion of a large part of all incident IPF patients in two ILD centres in the region increasing the generalizability of the results. In addition, we included patients immediately after their IPF diagnoses, thus reducing recall bias of important information, such as the date of symptom onset. However, as most patients experienced a diagnostic delay of several years, there remains a risk of recall bias in our cohort. Wherever possible, time points were extracted from electronic medical records, resulting in more reliable data compared with surveys with patient reported data. However, some data were still patient reported, and thus not entirely objective. This includes the date of symptom onset and the first healthcare contact. These data are inherently subjective and could not have been collected in a different manner. The definition of symptom onset can also be debated. Many patients with IPF have comorbidities which could give respiratory symptoms (i.e., cardiovascular disease or COPD) making it difficult to define the onset of symptoms caused by IPF. However, proven obstructive pulmonary disease was not a risk factor for a prolonged delay.
Our study was performed in one single country and findings cannot simply be generalized to other countries and healthcare systems. While treatment of IPF in Denmark is centralised to a few ILD centres, it may not be in other countries, potentially leading to more missed or delayed diagnoses. Also, the organization and responsibilities of primary, secondary and tertiary care differ between countries. Due to these differences, we considered the combined healthcare delay in the statistical analyses, rather than the specific delays (general practitioner, community hospital or ILD centre). Nevertheless, we believe that patients with IPF in other health systems will meet the same obstacles on their path towards a diagnosis of IPF, due to the rarity of the condition and the difficulty in establishing a confident diagnosis.